In:
Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 3, No. 20 ( 2018-02-09)
Abstract:
The human leukocyte antigen–A2 (HLA-A2)–restricted zinc transporter 8 186–194 (ZnT8 186–194 ) and other islet epitopes elicit interferon-γ secretion by CD8 + T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8 186–194 -reactive CD8 + T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8 + T cells reactive to ZnT8 186–194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8 186–194 -reactive CD8 + T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8 186–194 -reactive CD8 + T cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8 + T cells. In contrast, ZnT8 186–194 -reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8 + T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.
Type of Medium:
Online Resource
ISSN:
2470-9468
DOI:
10.1126/sciimmunol.aao4013
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2018
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